Apoptosis in breast cancer as related to histopathological characteristics and prognosis

Lipponen, P; Aaltomaa, S.; Kosma, Veli‐Matti; Syrjänen, Karí

doi:10.1016/0959-8049(94)00342-3

Cited by 189 publications

(168 citation statements)

References 18 publications

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“…In multivariate analysis, it was proved that TUNEL-I had independent prognostic value. A similar association between high apoptotic rate and poor prognosis has been described in other tumors (e.g., non-small cell lung carcinoma (31), breast carcinoma (32), and ovarian carcinoma (27)). Because it is widely known that elevated cell proliferation generally is associated with poor prognosis in many cancers, including synovial sarcoma (4, 5,), the association between high apoptotic rate and poor prognosis in synovial sarcoma could be explained by the correlation between apoptosis and cell proliferation.…”

Section: Discussionsupporting

confidence: 75%

Prognostic Significance of Apoptosis in Synovial Sarcoma: Correlation with Clinicopathologic Parameters, Cell Proliferative Activity, and Expression of Apoptosis-Related Proteins

et al. 2000

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bcl-2 overexpression in synovial sarcomas has been recently reported. Although it is widely known that bcl-2 suppresses apoptosis in various cells, there are no studies that have examined the significance of apoptosis in synovial sarcoma. In the present study, we visualized apoptotic tumor cells by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate in situ nick end-labeling (TUNEL) method in 49 cases of primary synovial sarcoma. The degree of apoptosis was analyzed in relation to several clinicopathologic parameters, cell proliferative activity, and immunohistochemical expression of apoptosis-related proteins, including bcl-2, bax, bcl-x, bak, p53, p21 (WAF1/CIP1), Fas, and Fas ligand. TUNEL index (TUNEL-I) significantly correlated with the mitotic index (MI) (ñ ‫؍‬ 0.60, P < .0001) and Ki-67 labeling index (MIB1-I) (ñ ‫؍‬ 0.52, P ‫؍‬ 0.0005). There was a highly significant association between high TUNEL-I value (>.8%) and poor prognosis (log-rank test; P < .0001). Many synovial sarcomas were diffusely positive for bcl-2 family proteins (bcl-2, bax, bcl-x, and bak) and were negative or only sporadically positive for Fas, Fas ligand, p53, and p21 (WAF1/CIP1) proteins. The results indicated that increased rate of apoptosis in primary synovial sarcoma was considered to be an indicator of poor prognosis. In addition, apoptosis in synovial sarcoma may be controlled by multiple apoptosis-regulating mechanisms, including the bcl-2 family.

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Section: Discussionsupporting

confidence: 75%

Prognostic Significance of Apoptosis in Synovial Sarcoma: Correlation with Clinicopathologic Parameters, Cell Proliferative Activity, and Expression of Apoptosis-Related Proteins

et al. 2000

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“…Necrosis could occur by either of the mechanisms of cell death resulting from programmed apoptosis; these include cell death associated with squamous differentiation or that resulting from accidental ischaemia occurring in the centre of individual cancer cell nests (Majno and Joris, 1995). It is also shown that the number of apoptotic cancer cells is higher in tumours showing high-grade atypia and necrosis (Lipponen et al, 1994).…”

Section: Discussionmentioning

confidence: 98%

Squamoid features and expression of involucrin in primary breast carcinoma associated with high histological grade, tumour cell necrosis and recurrence sites

Tsuda

Sakamaki²,

Fukutomi³

et al. 1997

Br J Cancer

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Summary Although breast carcinomas are considered to originate from glandular epithelial cells, some exhibit 'squamoid features', comprising stratification with a gradient in the nuclear-cytoplasmic ratio within individual cancer cell nests on microscopy. In parallel with a histological review of squamoid features, we immunohistochemically investigated the expression of involucrin, a marker of terminal squamous differentiation, in 223 breast carcinomas with one to three regional nodal metastases but no distant metastases and analysed their association with other clinicopathological parameters to explore their clinical and biological implications. Squamoid features and involucrin expression, detected in 22% and 27% of cases respectively, correlated with each other and were associated with high-grade atypia, a solidnest pattern, cancer cell necrosis on histology and negative oestrogen receptor status. The incidence of regional recurrences was higher in patients with involucrin expression, whereas bone metastases were less frequent in groups with squamoid features or with diffuse (> 10%) involucrin expression. Both squamoid features and involucrin expression, which were considered to be derived either from differentiation into keratinocytes or from some kind of cellular degeneration caused by high turnover rate, are suggested to influence the biological behaviour of breast cancer cells in vivo, and they may be effective in predicting the most likely recurrence sites.

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“…In human breast cancer, Bcl-2 is suggested to inhibit apoptosis, and lower frequency of apoptosis is reported to be a better prognosis marker. 48,49 In this context, KGF might inhibit apoptosis through the elevation of Bcl-2 level in human breast cancer, and coexpression of KGF and KGFR could be correlated with a better prognosis, though the direct relationship between KGF expression and prognosis remains unclear at present.…”

Section: Discussionmentioning

confidence: 99%

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

Tamaru

Hishikawa

Ejima

et al. 2004

Laboratory Investigation

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Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecular mechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocyte growth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediating estrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependent tissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expression patterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies and nonradioactive in situ hybridization with T-T dimerized synthetic oligonucleotide probes. We next compared the results with the expression of estrogen receptor (ER) a and b, proliferative activity and apoptotic frequency (TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ERpositive (MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In the surgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), while KGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis of both KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated with the expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNEL index, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detected only in ER a-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect of KGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate that ER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, in human breast cancer. Keywords: apoptosis; breast cancer; estrogen receptor; immunohistochemistry; in situ hybridization; keratinocyte growth factor; TUNEL staining Breast cancer is the most frequent malignant tumor of women in the USA and European countries. In Japan, the frequency of breast cancer has rapidly increased during the last decade, and currently approximately 20 000 women develop breast cancer per year. However, our knowledge of the development and progression of breast cancer is still largely limited. The proliferation and differentiation of breast cancer cells are influenced by estrogen, 1-3 which exerts its action through binding to estrogen receptor (ER). Currently, ER is categorized into two subtypes, ER a and b, and both are believed to act as an active transcription factor, which binds to a specific DNA segment such as the estrogen responsive element (ERE) and AP-1 site, to regulate the expression of a variety of genes. 4,5 The majority of human breast cancer cells express both ER a and ER b. 6 While ER a is regarded as an indicator of

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Apoptosis in breast cancer as related to histopathological characteristics and prognosis

Cited by 189 publications

References 18 publications

Prognostic Significance of Apoptosis in Synovial Sarcoma: Correlation with Clinicopathologic Parameters, Cell Proliferative Activity, and Expression of Apoptosis-Related Proteins

Prognostic Significance of Apoptosis in Synovial Sarcoma: Correlation with Clinicopathologic Parameters, Cell Proliferative Activity, and Expression of Apoptosis-Related Proteins

Squamoid features and expression of involucrin in primary breast carcinoma associated with high histological grade, tumour cell necrosis and recurrence sites

Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer

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